PBPK Modeling of Lamotrigine and Efavirenz during Pregnancy: Implications for Personalized Dosing and Drug-Drug Interaction Management.

This study aimed to model the pharmacokinetics of lamotrigine (LTG) and efavirenz (EFV) in pregnant women using physiologically based pharmacokinetic (PBPK) and pregnancy-specific PBPK (p-PBPK) models. For lamotrigine, the adult PBPK model demonstrated accurate predictions for pharmacokinetic parameters. Predictions for the area under the curve (AUC) and peak plasma concentration (Cmax) generally agreed well with observed values. During pregnancy, the PBPK model accurately predicted AUC and Cmax with a prediction error (%PE) of less than 25%. The evaluation of the EFV PBPK model revealed mixed results. While the model accurately predicted certain parameters for non-pregnant adults, significant discrepancies were observed in predictions for higher doses (600 vs. 400 mg) and pregnant individuals. The model's performance during pregnancy was poor, indicating the need for further refinement to account for genetic polymorphism. Gender differences also influenced EFV pharmacokinetics, with lower exposure levels in females compared to males. These findings highlight the complexity of modeling EFV, in general, but specifically in pregnant populations, and the importance of validating such models for accurate clinical application. The study highlights the importance of tailoring dosing regimens for pregnant individuals to ensure both safety and efficacy, particularly when using combination therapies with UGT substrate drugs. Although drug-drug interactions between LTG and EFV appear minimal, further research is needed to improve predictive models and enhance their accuracy.

Transporter-mediated drug-drug interactions: regulatory guidelines, in vitro and in vivo methodologies and translation, special populations, and the blood-brain barrier.

This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.

Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients.

STUDY OBJECTIVE: Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily). DESIGN: Adult and pediatric PBPK models for LPV/RTV with rifampin were developed, including CYP3A and P-glycoprotein inhibition and induction. SETTING (OR DATA SOURCE): Data for LPV/RTV model development and evaluation were available from the pediatric AIDS Clinical Trials Group. PATIENTS: Dosing simulations were next performed to optimize dosing in children (2 months to 8 years of age). INTERVENTION: Exposure following super-boosted LPV/RTV with 10 and 15 mg/kg PO daily rifampin was simulated. MEASUREMENTS AND MAIN RESULTS: Simulated parameters were within twofold observations for LPV, RTV, and rifampin in adults and children ≥2 weeks old. The model predicted that, in healthy adults receiving 400/100 mg oral LPV/RTV twice daily (BID), co-treatment with 600 mg oral rifampin daily decreased the steady-state area under the concentration vs. time curve of LPV by 79%, in line with the observed change of 75%. Simulated and observed concentration profiles were comparable for LPV/RTV (230/57.5 mg/m2 ) PO BID without rifampin and 230/230 mg/m2 LPV/RTV PO BID with 10 mg/kg PO daily rifampin in pediatric patients. Sixteen mg/kg of super-boosted LPV (LPV/RTV 1:1) PO BID with 15 mg/kg PO daily rifampin achieved simulated LPV troughs >1 mg/L in ≥93% of virtual children weighing 3.0-24.9 kg, which was comparable with 10 mg/kg PO daily rifampin. CONCLUSIONS: Super-boosted LPV/RTV with 15 mg/kg rifampin achieves therapeutic LPV troughs in HIV/TB-infected simulated children.

Investigation of cytochrome P450 inhibitory properties of deoxyshikonin, a bioactive compound from Lithospermum erythrorhizon Sieb. et Zucc.

Deoxyshikonin, a natural naphthoquinone compound extracted from Lithospermum erythrorhizon Sieb. et Zucc (Boraginaceae), has a wide range of pharmacological activities, including anti-tumor, anti-bacterial and wound healing effects. However, the inhibitory effect of deoxyshikonin on cytochrome P450 (CYP) remains unclear. This study investigated the potential inhibitory effects of deoxyshikonin on CYP1A2, 2B1/6, 2C9/11, 2D1/6, 2E1 and 3A2/4 enzymes in human and rat liver microsomes (HLMs and RLMs) by the cocktail approach in vitro. The single-point inactivation experiment showed that deoxyshikonin presented no time-dependent inhibition on CYP activities in HLMs and RLMs. Enzyme inhibition kinetics indicated that in HLMs, deoxyshikonin was not only a competitive inhibitor of CYP1A2 and 2E1, but also a mixed inhibitor of CYP2B6, 2C9, 2D6 and 3A4, with Ki of 2.21, 1.78, 1.68, 0.20, 4.08 and 0.44 µM, respectively. In RLMs, deoxyshikonin not only competitively inhibited CYP2B1 and 2E1, but also exhibited mixed inhibition on CYP1A2, 2C11, 2D1 and 3A2, with Ki values of no more than 18.66 µM. In conclusion, due to the low Ki values of deoxythiokonin on CYP enzymes in HLMs, this may lead to drug-drug interactions (DDI) and potential toxicity.

Minimization of the Drug and Gene Interactions in Polypharmacy Therapies Augmented with COVID-19 Medications.

Medications Dexamethasone, Remdesivir or Colchicine, used to treat COVID-19 patients, have significant interactions with other medications and the human genome. The study presented in this paper investigates how to use the Personalized Medicine Therapy Optimization Method (PM-TOM) to minimize these interactions in polypharmacy therapies of COVID-19 patients. We applied PM-TOM on the EMR database of Harvard Personal Genome Project (PGP), drug database DrugBank and Comprehensive Toxicogenomics Database (CTD) to analyze polypharmacy therapies augmented with these medications. The main finding is that these COVID-19 medications significantly increase the drug and gene interactions in partially optimized (or unoptimized) therapies, which is not the case in the fully optimized ones. For example, the test results show that in polypharmacy treatments for patients having between 3 and 8 conditions, the average number of drug and gene interactions in partially optimized therapies ranges from 3 to 18 after adding Remdesivir, 4.3 to 20 Colchicine, and 4.7 to 23 Dexamethasone. On the other hand, these interactions in fully optimized therapies range only 0.6 to 5.2, 1.2 to 7, and 2.7 to 11, respectively. These results suggest that polypharmacy therapies should be carefully examined before adding these medications. This recommendation applies to all other situations when polypharmacy patients may conduct new serious conditions, such as COVID-19, requiring additional medications with a high number of drug and gene interactions.

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

(1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0-2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43-89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096-0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

A broad-spectrum substrate for the human UDP-glucuronosyltransferases and its use for investigating glucuronidation inhibitors.

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drug/herb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O-glucuronidated by all tested human UGTs, including the typical N-glucuronidating enzymes UGT1A4 and UGT2B10. MOA-O-glucuronidation yielded a single mono-O-glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA-O-glucuronidation activity assay, which was then used for investigating MOA-O-glucuronidation kinetics in recombinant human UGTs. The derived Km values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors.

A fluorescence-based microplate assay for high-throughput screening and evaluation of human UGT inhibitors.

Human UDP-glucuronosyltransferase enzymes (hUGTs), one of the most important classes of conjugative enzymes, are responsible for the glucuronidation and detoxification of a variety of endogenous substances and xenobiotics. Inhibition of hUGTs may cause undesirable effects or adverse drug-drug interactions (DDI) via modulating the glucuronidation rates of endogenous toxins or the drugs that are primarily conjugated by the inhibited hUGTs. Herein, to screen hUGTs inhibitors in a more efficient way, a novel fluorescence-based microplate assay has been developed by utilizing a fluorogenic substrate. Following screening of series of 4-hydroxy-1,8-naphthalimide derivatives, we found that 4-HN-335 is a particularly good substrate for a panel of hUGTs. Under physiological conditions, 4-HN-335 can be readily O-glucuronidated by ten hUGTs, such reactions generate a single O-glucuronide with a high quantum yield (Ф = 0.79) and bring remarkable changes in fluorescence emission. Subsequently, a fluorescence-based microplate assay is developed to simultaneously measure the inhibitory effects of selected compound(s) on ten hUGTs. The newly developed fluorescence-based microplate assay is time- and cost-saving, easy to manage and can be adapted for 96-well microplate format with the Z-factor of 0.92. We further demonstrate the utility of the fluorescence-based assay for high-throughput screening of two compound libraries, resulting in the identification of several potent UGT inhibitors, including natural products and FDA-approved drugs. Collectively, this study reports a novel fluorescence-based microplate assay for simultaneously sensing the residual activities of ten hUGTs, which strongly facilitates the identification and characterization of UGT inhibitors from drugs or herbal constituents and the investigations on UGT-mediated DDI.

Quantitative analysis of an impact of P-glycoprotein on edoxaban's disposition using a human physiologically based pharmacokinetic (PBPK) model.

The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively.

Current use of anticholinergic medications in a large naturalistic sample of psychiatric patients.

Due to the high number of psychotropic drugs with anticholinergic potential, patients taking psychotropic drugs are at high risk for anticholinergic adverse drug reactions (ADRs). The aim of this study was to analyze the prevalence and type of pharmacodynamic anticholinergic drug-drug interactions in psychiatric patients. The retrospective longitudinal analysis used data from a large pharmacovigilance study conducted in ten German psychiatric hospitals. Anticholinergic burden of drugs was defined as "strong" or "moderate" based on current literature. Number and type of anticholinergic drugs were assessed. In total, 27,396 patient cases (45.6% female) with a mean age of 47.3 ± 18.3 years were included. 17.4% (n = 4760) of patients were ≥ 64 years. 35.4% of the patients received between one and four anticholinergic drugs simultaneously. A combination of drugs with anticholinergic potential was detected in 1738 cases (6.3%). Most prescribed drugs were promethazine (n = 2996), olanzapine (n = 2561), biperiden (n = 1074), and doxepin (n = 963). Patients receiving anticholinergic combinations were younger (45.7 vs. 47.4 years, p < 0.01) and had a longer inpatient stay (median 18 vs. 26.5 days, p < 0.001). The prevalence of anticholinergic drug use in psychiatry is high. Further efforts need to focus on reducing the rate of anticholinergics and inappropriate medication especially in the elderly. Anticholinergic ADRs can be prevented by avoiding high-risk drug combinations. Replacing tricyclic antidepressants and first-generation antihistamines with drugs with lower anticholinergic potential and avoiding biperiden could reduce 59.3% of anticholinergic drug application.

Scutellarin is Highly Likely to be Responsible for Drug-Drug Interactions Mediated by Hepatic Organic Anion-Transporting Polypeptide1B3.

PURPOSE: Scutellarin, a flavonoid derived from the plant Erigeron breviscapus, is currently widely used to treat cerebrovascular diseases, liver-related diseases, and hyperlipidemia in china and other East Asian countries. This study was to investigate the effect of scutellarin on the uptake of rosuvastatin in HEK293T cells expressing human organic anion transporting polypeptide 1B3 (hOATP1B3) and rat OATP1B2 (rOATP1B2), respectively, and the effect of scutellarin on the pharmacokinetics of rosuvastatin in rats. METHODS: The newly established HEK293T cells expressing hOATP1B3 and rOATP1B2 were used to examine the effects of scutellarin and positive controls on in vitro rosuvastatin transport. After co-feeding with scutellarin, the rosuvastatin area under the plasma concentration-time curve (AUC0-24h), the peak plasma drug concentration (Cmax), elimination half-life (t1/2), time to reach Cmax (tmax), clearance (CL) and apparent clearance (CL/F) of rosuvastatin were determined in rats. RESULTS: Scutellarin inhibited hOATP1B3- and rOATP1B2-mediated rosuvastatin uptake (IC50: 45.54 ± 6.67 µM and 27.58 ± 3.97 µM) in vitro in a concentration-dependent manner. After co-feeding with scutellarin, the AUC0-24h and Cmax of rosuvastatin in rats increased to 27.4% and 37.7%, respectively. The t1/2 and tmax of rosuvastatin showed no significant change. Moreover, scutellarin caused 29.2% and 28.1% decrease in the CL and CL/F of rosuvastatin. CONCLUSION: Scutellarin may inhibit the hOATP1B3- and rOATP1B2-mediated transport of rosuvastatin in vitro, and exerts a moderate inhibitory effect on the pharmacokinetics of rosuvastatin in rats. Scutellarin is highly likely to participate in drug-drug interactions, as mediated by OATP1B3 in humans.

Using PM-TOM for the Minimization of Adverse Drug and Gene Interactions in Therapies for Common Multi-Diseases.

Multiple studies show that therapies for multi-diseases can lead to dangerous reactions and high healthcare costs due to their adverse drug-drug, drug-gene, and drug-condition interactions. In this paper, we present the results of using PM-TOM (Personalized Medicine Therapy Optimization Method) for finding therapies that minimize these interactions. The testing of the method was performed on the repository of electronic medical records of the Harvard Personal Genome Project (PGP), and the public databases of the drug and genetic information: DrugBank and Comprehensive Toxicogenomics Database (CTD). The results presented in this paper showed a significant potential of PM-TOM for reducing the cumulative adverse drug interactions in therapies for common multi-diseases.

Discontinuation and dose adjustment of metoprolol after metoprolol-paroxetine/fluoxetine co-prescription in Dutch elderly.

PURPOSE: Co-prescription of paroxetine/fluoxetine (a strong CYP2D6 inhibitor) in metoprolol (a CYP2D6 substrate) users is common, but data on the clinical consequences of this drug-drug interaction are limited and inconclusive. Therefore, we assessed the effect of paroxetine/fluoxetine initiation on the existing treatment with metoprolol on the discontinuation and dose adjustment of metoprolol among elderly. METHODS: We performed a cohort study using the University of Groningen IADB.nl prescription database (www.IADB.nl). We selected all elderly (≥60 years) who had ever been prescribed metoprolol and had a first co-prescription of paroxetine/fluoxetine, citalopram (weak CYP2D6 inhibitor), or mirtazapine (negative control) from 1994 to 2015. The exposure group was metoprolol and paroxetine/fluoxetine co-prescription, and the other groups acted as controls. The outcomes were early discontinuation and dose adjustment of metoprolol. Logistic regression was applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Combinations of metoprolol-paroxetine/fluoxetine, metoprolol-citalopram, and metoprolol-mirtazapine were started in 528, 673, and 625 patients, respectively. Compared with metoprolol-citalopram, metoprolol-paroxetine/fluoxetine was not significantly associated with the early discontinuation and dose adjustment of metoprolol (OR = 1.07, 95% CI:0.77-1.48; OR = 0.87, 95% CI:0.57-1.33, respectively). In comparison with metoprolol-mirtazapine, metoprolol-paroxetine/fluoxetine was associated with a significant 43% relative increase in early discontinuation of metoprolol (OR = 1.43, 95% CI:1.01-2.02) but no difference in the risk of dose adjustment. Stratified analysis by gender showed that women have a significantly high risk of metoprolol early discontinuation (OR = 1.62, 95% CI:1.03-2.53). CONCLUSION: Paroxetine/fluoxetine initiation in metoprolol prescriptions, especially for female older patients, is associated with the risk of early discontinuation of metoprolol.

The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.

PURPOSE: Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. METHOD: Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. RESULTS: A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. CONCLUSION: Despite the signalling software, metoprolol-paroxetine/fluoxetine combinations are still observed in the elderly population. The clinical impact of these interactions needs further investigation. Copyright © 2017 John Wiley & Sons, Ltd.

Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases.

Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68µM and 30.82µM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.